This invention relates to a method for treatment of hyperproliferative tissues, such as tumors and hyperproliferative blood vessels, e.g. those associated with age related macular degeneration (AMD), using photodynamic methods. Certain photodynamic compounds, e.g. porphyrin related compounds such as derivatives of chlorins, bacteriochlorins and hematoporphyrins such as porfimer sodium compounds, when stable, may be used for that purpose. These compounds have the ability to preferentially collect in hyperproliferative tissues when injected into an organism and to absorb light to cause reduction in growth of the tissue, such as by its destruction. Such reduction in growth of hyperproliferative tissue using photodynamic compounds is collectively referred to herein as photodynamic therapy.
Photodynamic therapy (PDT) is a relatively new modality for the treatment of various types of solid tumors. Many porphyrins and related photosensitive compounds demonstrate the ability to selectively accumulate in neoplastic tissue after intravenous injection and sensitize the tissue to photoirradiation. Activation of the photosensitive agent by visible light, delivered by a laser through fiber optics, results in the generation of cytotoxic agents. It is currently accepted that the production of singlet oxygen, formed from molecular oxygen, formed from molecular oxygen by the transfer of energy directly or indirectly from the activated photosensitizer, is responsible for tumor homeostasis and the observed tumor destruction.
Following absorption of light, the photosensitizer is transformed from its ground singlet state (P) into an electronically excited triplet state (3P*; xcfx84xcx9c10xe2x88x922 sec.) via a short-lived excited singlet state (1P*; xcfx84xcx9c10xe2x88x926 sec.) The excited triplet can undergo non-radiative decay or participate in an electron transfer process with biological substrates to form radicals and radical ions, which can produce singlet oxygen and superoxide (O2xe2x88x92) after interaction with molecular oxygen (O2). Singlet oxygen is the key agent responsible for cellular and tissue damage in PDT, causing oxidation of the target tissue (T); there also is evidence that superoxide ion may be involved.
In 1978, it was reported that a combination of hematoporphyrin derivative (HpD) and light was effective in causing partial or complete tumor necrosis in 111 of 113 tumors in 25 patients. PDT with Photofrin(copyright), a purified HpD, has been approved in Canada for bladder and esophageal cancer; in the Netherlands and France for early and advanced stage esophageal cancer; in Japan for early stage lung, esophageal, gastric, and cervical cancer; and in the United States for advanced stage esophageal and lung cancers. More than 10,000 patients worldwide have been treated with PDT for a multiplicity of tumors accessible to light, including skin, lung, bladder, head and neck, breast, and esophageal cancers. PDT exerts its antitumor effect by several mechanisms, e.g. direct toxicity to tumor cells, occlusion and dissolution of tumor vasculature and microvasculature. In spite of these modes of operation, a number of PDT treated tumors are not cured. Further PDT has little or no effect upon metastatic lesions not exposed to light. In addition, known photodynamic compounds are often ineffective against hypoxic tumor cells and do little to enhance immune response of the organism to undesired hyperproliferative tissue. Therefore, photodynamic therapy, while effective, is not as effective as desired and a method for improving overall efficacy is needed.
Chemotherapy is used a) as adjuvant treatment before and after local treatment for primary disease, with the aim of eradicating occult metastasis and b) in combination with other modalities, including other chemotherapeutic drugs, in an attempt to improve their therapeutic effects. This synergy does not lead to therapeutic benefit unless the interaction between the effects is tumor specific. There has been a recent interest in using biological response modifiers (BRM) as single or adjuvant therapies against cancer. BRMs consist of a large number of molecules that may act to regulate various components of the immune response or other defense mechanisms.
The development of agents that can stimulate or augment the host""s immune response against malignancies represents an attractive approach to cancer therapy. Flavone-8-acetic acid (FIG. 1a) is a synthetic flavonoid widely studied in the mid-1980s through 1990s as an agent to treat solid tumors. FAA exerts its antitumor activity, at least in part, by interrupting tumor vascular supply. For example various investigators, using dye perfusion, NMR, RbCl-uptake and Xe-clearance techniques, have shown that FAA causes reduction in tumor blood flow. Little or no alteration in normal tissue blood flow has been observed. While FAA shows in vitro activity against a number of tumor cell lines, in vivo effects, primarily hemorrhagic tumor necrosis are similar to those described following treatment with TNF. FAA induces natural killer cell activity in spleen and other tissues. A comparison of in vitro and in vivo studies using the Lewis lung carcinoma strongly suggested an indirect mode of antitumor action. Mahadevan et al. demonstrated that pretreatment of mice with antiserum to TNF-xcex1 could almost completely abrogate the reduction in Colon 26 tumor blood flow induced by FAA. In the same study, FAA was shown to induce in vitro splenocytes and peritoneal exudate cells to produce and release material with TNF-xcex1-like activity (as determined in a functional assay using TNF-sensitive WEHI 164 cells). These observations suggest that the activity of FAA can be attributed to its ability to induce TNF-xcex1 in tumors.
In spite of the impressive preclinical activity of FAA, clinical trials have been disappointing due to lack of potency and dose limiting toxicity. Structure-activity studies of analogs of FAA were undertaken to find compounds with similar biological profiles but with increased clinical effectiveness. In the earliest study the topologically related mono-substituted fused-ring analog Xanthenone-4-acetic acid (XAA) proved more efficient than FAA in eliminating Colon 38 tumors. Subsequently, a study by the same group showed that some di-substituted derivatives of XAA, in particular 5,6-Dimethylxanthenone-4-acetic acid (DMXAA; FIG. 1b), had considerably greater dose potencies than FAA against implanted murine tumors. Like FAA, DMXAA has been shown to induce TNF-xcex1 along with IFN-xcex3. The TNF-xcex1 is produced almost entirely within the tumor by both tumor cells and tumor-infiltrated host cells. Circulating TNF is markedly lower than that obtained by injecting therapeutic levels of TNF-xcex1 or by endogenous induction of TNF-xcex1 by LPS administration. This results in a selective tumor response with moderate systemic toxicity. DMXAA, in contrast to FAA, is active in vitro against cultured human and murine cells. It has been shown that exogenous rHuTNF-xcex1 potentiates PDT without a concomitant increase in either local or systemic toxicity.
It is therefore an object of the invention to improve effectiveness of photodynamic compounds against hyperproliferative tissue including hypoxic tumor cells, to enhance immune response of the organism to undesired hyperproliferative tissue and to provide effectiveness even in the absence of exposure to light.
In accordance with the invention a novel method is provided for treating undesired hyperproliferative tissue in a mammal. The method includes the steps of: injecting the mammal with a photodynamic compound having a selective uptake in the hyperproliferative tissue and which is activated at a particular light frequency; injecting the mammal with a xanthenone-4-acetic acid or a Group I metal, Group II metal or quaternary salt thereof near the time of maximum uptake of the photodynamic compound in the hyperproliferative tissue; and exposing the hyperproliferative tissue to light at the particular frequency that activates the photodynamic compound.
The method of the invention causes necrosis of the hyperproliferative tissue to an extent greater than can be obtained by either the photodynamic compound or xanthenone-4-acetic acid alone. Further and surprisingly the method enhances immune response of the mammal to the hyperproliferative tissue even after the photodynamic compound and xanthenone-4-acetic acid are no longer present in the mammal.